Eur J Nucl Med Mol Imaging (2011) 38:2153–2164 DOI 10.1007/s00259-011-1903-0
ORIGINAL ARTICLE
Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide Eric Frampas & Catherine Maurel & Patricia Remaud-Le Saëc & Thibault Mauxion & Alain Faivre-Chauvet & François Davodeau & David M. Goldenberg & Manuel Bardiès & Jacques Barbet
Received: 19 May 2011 / Accepted: 2 August 2011 / Published online: 20 August 2011 # Springer-Verlag 2011
Abstract Purpose We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses. Methods LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for 131I, 177 Lu, 90Y, 211At, and 213Bi using realistic specific activities. Results Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15–24 h), tumor uptake reached ∼9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), 211At is predicted to deliver a high absorbed E. Frampas (*) : C. Maurel : P. Remaud-Le Saëc : T. Mauxion : A. Faivre-Chauvet : F. Davodeau : M. Bardiès : J. Barbet Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Université de Nantes, Inserm, UMR 892, 8 quai Moncousu, BP 70721, 44007 Nantes cedex 1, France e-mail:
[email protected] D. M. Goldenberg Immunomedics, Inc., Morris Plains, NJ, USA D. M. Goldenberg Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ, USA
dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. 90Y and 213 Bi would also deliver high absorbed doses to tumor (18.6 for 90Y and 26.5 Gy for 213Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity. Conclusion Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially 211At, with kidneys being the dose-limiting organ. 177Lu and 131I should be considered for repeated injections. Keywords Radioimmunotherapy . Pretargeting . Bispecific antibody . Colonic cancer . Mice . Radionuclide
Introduction Despite screening campaigns, more than 20% of patients with colorectal cancer will be diagnosed with hepatic metastases and have a spontaneous 5-year survival of only 0–1% [1]. Improvement in chemotherapy has resulted in a significant survival improvement (20.3 vs 15.6 months) [2], but surgery remains the only curative treatment. Radiosensitive hematologic malignancies, such as non-Hodgkin’s lymphoma, have benefitted from radioimmunotherapy (RIT), a targeted radiotherapy directed against tumor-associated antigens. Nevertheless, RIT has not been as successful in solid
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malignancies. The major reasons are a low radiosensitivity and a difficult penetration of the antibodies in solid tumors, reducing the absorbed dose achieved [3]. Dosimetry data previously demonstrated that RIT delivers
